Patients infected with human-deficiency virus (HIV)-1 resulting in the development of acquired immune deficiency syndrome (AIDS) often develop neurological disease named AIMS Dementia Complex (ADC). The underlying basis of ADC is not clearly understood. Models proposed include a direct toxicity of HIV proteins or production of soluble factors interacting with N-methyl D-aspartate (NMDA) receptors. It has been reported that the level of quinolinic acid, an NMDA receptor excitotoxin, was elevated in AIDS patients, which correlated with the severity of neuropsychological dysfunction. Quinolinic acid is a product of tryptophan metabolism, and it is induced by interferon-gamma apparently through the induction of indoleamine 2,3-dioxygenase (INDO), the first enzyme in the extra hepatic metabolism of tryptophan. Tryptophan is also the precursor for the production of serotonin, an important neurotransmitter. We propose to study whether IFN-gamma-inducible INDO enzyme is a key factor responsible for elevated production of quinolinic acid and serotonin deficiency found in AIDS patients suffering from ADC. In Phase I of this project, we will transfect cells with INDO cDNA cloned in an inducible expression vector and determine whether expression of INDO enzyme would lead to enhanced production of quinolinic acid and diminished production of serotonin. In the event of a direct link between INDO and metabolic changes in quinolinic acid and serotonin, in the Phase II of this project, we will make transgenic mice expressing INDO in attempts to develop a mouse model of this disease for further studies towards intervention and development of therapeutic approaches. PROPOSED COMMERCIAL APPLICATION: The proposed study would determine whether the elevated expression of indoleamine 2,3-dioxygenase is a key factor responsible for the metabolic changes in quinolinic acid and serotonin in AIDS patients. This will identify a target for intervention and development of therapeutic approaches for the neurological disease associated with AIDS.